Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

Hellard, Stéphanie Le; Mühleisen, Thomas W.; Djurovic, Srdjan; Fernø, Johan; Ouriaghi, Z; Mattheisen, Manuel; Vasilescu, Catalina; Ræder, Maria B.; Hansen, Thomas Folkmann; Strohmaier, Jana; Georgi, Alexander; Brockschmidt, Felix F.; Melle, Ingrid; Nenadić, Igor; Sauer, Heinrich; Rietschel, Marcella; Nöthen, Markus M.; Werge, Thomas; Andreassen, Ole A.; Cichon, Sven; Steen, Vidar M.

doi:10.1038/mp.2008.110

Cited by 72 publications

(60 citation statements)

References 62 publications

(70 reference statements)

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“…Some notable top-ranked genes associated with sp-DMNS2 connectivity, such as DGKH, whose differential effects were shown recently to manifest as a failure to disengage DMN during a verbal fluency task in subjects at high familial risk of BP, were candidates (75). Another top-ranked gene, SREBF2, a lipid homeostasis regulator, has been shown previously to be associated with SZ (76). Neuronal plasticity/synaptic regulators such as KALRN also were Fig.…”

Section: Ica Derived Dmnsmentioning

confidence: 99%

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia

Meda

Ruaño

Windemuth

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

213

159

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The brain's default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders. However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown. Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach. The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/ or endophenotype status. A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging-genetic relationships. ICA identified three DMNs. Hypoconnectivity was observed in both patient groups in all DMNs. Similar patterns observed in SZREL were restricted to only one network. DMN connectivity also correlated with several symptom measures. Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks. Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes. Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses. In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL. Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity. The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases.genetics | BSNIP | architecture | molecular S chizophrenia (SZ) and psychotic bipolar disorder (PBP) are common, serious, heritable, genetically complex illnesses, sharing multiple characteristics, including risk genes and abnormalities in cognition, neural function, and brain structure (1-4). However, despite recent advances, their underlying biological mechanisms are largely undetermined and may be shared across the two diagnostic groups. Recent large-scale analyses have used various statistical informatics strategies to dissect these biological underpinnings better (5, 6). A recent study using a pathwayenrichment strategy showed that genes involved in neuronal cell adhesion, synaptic formation, and cell signaling are overrepresented in SZ and bipolar disorder (BP) (6). Another study using an informatics-based approach identified several cohesive genetic networks related to axon guidance, neuronal cell mobility, and synaptic functioning as key players in schizophrenia (5).Although risk for psychotic illnesses is driven in small part by highly penetrant, often private mutations such as copy number variants, substantial...

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Section: Ica Derived Dmnsmentioning

confidence: 99%

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia

Meda

Ruaño

Windemuth

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

213

159

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“…Mood stabilisers such as lithim and valproate are known to downregulate SREBP-I c (Raeder et al, 2006). Polymorphisms in SREBPI and SREBP2, two antipsy-chotic activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia (Le Hellard et al, 2008) and with type 2 diabetes mellitus (Liu et al, 2008). SREBP activation is an essential step in NMDAR-mediated excitotoxic neuronal death (Taghibiglou et al, 2009) and DNA microarray data show that stearoyl-COA desaturase-I, a SREBPIa target gene, is upregulated in human temporal lobe epilepsy (Arion et al, 2006).. Also, uric acid promotes lipogenesis through overexpression of acetyl-CoA carboxylase-I and fatty acid synthase via activation of SREBP-I c and this is antagonised by metformin (a known blocker of SREBP-I c) .…”

Section: Sterol Regulatory Element Binding Protein-i C In Mania Seizmentioning

confidence: 99%

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

Oriaifo¹

2015

J. Med. Med. Sci

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The prevalence of diabetes and co-morbid diseases, especially in developing countries, may have already exceeded estimates. Accumulating reports indicate considerable underpinnings in the mechanisms of the aetiopathogenesis of metabolic syndrome, bipolar disorder, epilepsy and, recently, substance addiction. Continuing evidence incriminates dysfunction in genetic, mitochondrial and inflammatory cascade mechanisms as contributory factors to the dysregulation of neurotrophic, serotonergic, dopaminergic, adrenergic, glutamatergic, GABAergic and autophagic pathways. There may also be co-incident dysregulation of the global anti-oxidant network, the endogenous digitalis system, the vasopressin signalling and the hypothalamo-pituitary-adrenal axis. Nuclear factor-kappa B (NF-kappa B) signaling and reactive oxygen species lead to activation of the mammalian target of rapamycin complex I (mTORCI) and this process may be central to the aetiopathogenesis of drug addiction, obesity, foetal programming, diabetes mellitus, epilepsy and bipolar disorder. Antiglycaemics such as cannabinoid CB2 agonists, metformin, artesunate and valproate; insulin-mimetics such as glucagon-like peptide-I (GLP-I) and its analogues; phytomedicines from garlic and curcumin are now shown to exhibit neuroprotective effects. These agents which may down-regulate inflammatory cytokines, upregulate endothelial nitric oxide (eNOS) and peroxisome proliferator-activated receptor alpha (PPAR-α) signalling, attenuate mitochondrial dysfunction, enhance the actions of glucagon-like peptide-I (GLP-I), inhibit mTOR, NF-kappa B, interleukin-I β and glycogen synthase kinase-3 β stand to be of benefit in these illnesses which demonstrate considerable overlay in their aetopathogenic mechanisms. Underpinnings and bidirectional relationships between the metabolic syndrome and mental health disorders may pave way for common new fronts to drug development in translational cardiovascular psychiatry and neurology.

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“…According to Gabriel and colleagues' (2002) haplotype block definition, the Dysbindin gene is covered by six haplotype blocks. We selected 38 haplotype tagging (h) SNPs from HapMap phase I+II data (HapMap release 20, dbSNP 125), which capture all haplotypes at a minimum frequency of 1% in the Utah population (CEU) of the Centre d'Etude du Polymorphisme Humain (CEPH) Project (for a detailed description of the marker selection procedure, see Treutlein et al 2009 andLe Hellard et al 2008). These markers also comprised SNPs in inter-block regions, SNPs that were associated with SCZ in the previous studies by Mutsuddi and colleagues (2006), and SNPs associated with cognitive performance in SCZ and healthy controls ( Table 1).…”

Section: Snp Genotypingmentioning

confidence: 99%

A reappraisal of the association between Dysbindin (DTNBP1) and schizophrenia in a large combined case-control and family-based sample of German ancestry

Strohmaier¹,

Frank²,

Wendland³

et al. 2010

Gesundheitswesen

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Background-Dysbindin (DTNBP1) is a widely-studied candidate gene for schizophrenia (SCZ); however, inconsistent results across studies triggered skepticism towards the validity of the findings. In this HapMap-based study, we reappraised the association between Dysbindin and SCZ in a large sample of German ethnicity.Method-Six hundred thirty-four cases with DSM-IV SCZ, 776 controls, and 180 parentoffspring trios were genotyped for 38 Dysbindin SNPs. We also studied two phenotypicallydefined subsamples: 147 patients with a positive family history of SCZ (FH-SCZ+) and SCZ patients characterized for cognitive performance with Trail-Making Tests A and B (TMT-A: n=219; TMT-B: n=247). Given previous evidence of gene-gene interactions in SCZ involving the COMT gene, we also assessed epistatic interactions between Dysbindin markers and 14 SNPs in COMT. Results-No association was detected betweenDysbindin markers and SCZ, or in the FH-SCZ+ subgroup. Only one marker (rs1047631, previously reported to be part of a risk haplotype), showed a nominally significant association with performance on TMT-A and TMT-B; these findings did not remain significant after correction for multiple comparisons. Similarly, no pairwise epistatic interactions between Dysbindin and COMT markers remained significant after correction for 504 pairwise comparisons. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

Cited by 72 publications

References 62 publications

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia

Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

A reappraisal of the association between Dysbindin (DTNBP1) and schizophrenia in a large combined case-control and family-based sample of German ancestry

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